Stroma penetrating and immune modulating nanoparticles for image-guided therapy of pancreatic cancer

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Project Summary Resistance to therapy is the major challenge for the treatment of pancreatic cancer. Despite recent successes in immune checkpoint therapy of several human cancer types, pancreatic cancer showed a poor response to the immunotherapy. Increasing evidence reveals that a dense stromal barrier in pancreatic cancer blocks drug delivery and intratumoral distribution. The physical barrier of stromal and biological barrier from immunosuppressive responses further limit the number and function of infiltrating effector T cells. The objective of this project is to develop a new immunotherapy strategy by co-delivery of tumor penetrating and immunomodulating theranostic nanoparticles and PD-L1 inhibitors. Our innovative uPAR targeted and stroma breaking ligand consists of the amino terminal fragment (ATF) of uPA and the catalytic domain of matrix metalloproteinase-14 (ATFmmp14). It targets multiple cell types in tumors and promotes nanoparticle/drugs migrating through stromal and extracellular matrix barriers to reach tumor cells. ATFmmp14 conjugated magnetic iron oxide nanoparticle (IONP) carrying Doxorubicin or SN38 enabled magnetic resonance imaging (MRI) guided targeted delivery of nanoparticle/drug in tumors, and strong therapeutic effect in pancreatic cancer patient derived xenograft (PDX) and Kras-driven transgenic mouse tumor models. Notably, targeted delivery of the theranostic IONPs into tumors promoted infiltration of immune effector cells and decreased immunosuppressive cells, converting an immune “cold” pancreatic tumor into a “hot” tumor. We further developed an ultrasmall IONP PD-L1 inhibitor (Nano-iPD-L1) using an engineered PD-L1 blocking peptide. We showed that Nano-iPD-L1 selectively accumulated in pancreatic tumors following systemic delivery. Co-delivery of Nano-iPD-L1 with ATFmmp14-IONP/drug enhanced intratumroal delivery and significantly inhibited tumor growth in a mouse pancreatic cancer model. Therefore, we hypothesize that improved drug delivery in pancreatic tumors by co- administrations of stroma penetrating ATFmmp14-IONP/SN38 and Nano-iPD-L1 leads to a strong therapeutic efficacy through direct tumor cell killing, modulating immunosuppressive stroma, and blocking PD-L1 function to generate a strong response from cytotoxic T cells. In the proposed study, we will first investigate and optimize dose and therapeutic efficacy of co-delivery of ATFmmp14-IONP/SN38 and Nano-iPD-L1 in mouse pancreatic cancer models (Aim1). Followed by non-invasive MRI to assess theranostic IONP delivery and tumor response after the combined therapy using ATFmmp14-IONP/SN38 and Nano-iPD-L1 in transgenic mouse and pancreatic cancer PDX models (Aim 2). Finally, the effects of an enhanced intratumoral accumulation of ATFmmp14- IONP/SN38 and Nano-iPD-L1 on promoting infiltration of effector immune cells, modulating stromal immunosuppressive cells and factors, and activating cytotoxic T cells will be investigated in transgenic mouse pancreatic tumor models (Aim 3). Results of this study should provide us with new targeted theranostic IONPs and immunotherapy for translation of this novel therapy for advanced pancreatic cancer.